Mammalian hematopoietic stem cells and progenitor cells proliferate and differentiate into mature blood cells in close physical associations with the bone marrow stromal cells and the surrounding meshwork of proteins and glycoproteins. These cell-cell and cell- extracellular glycoprotein interactions not only provide anchorage to developing blood cells in the bone marrow, but they also influence the growth and development of blood cells in vitro. These cellular interactions become weaker as the developing blood cells become mature, eventually leading to the release of the mature but not the immature blood cells from the bone marrow into the circulating blood. The goal of the research is to understand the mechanisms by which developing red blood cells and pre-B lymphocytes interact with the bone marrow stroma, and to determine the role of these interactions in the hematopoietic cellular differentiation. The results of these investigations will be significant for several reasons. First, in chronic myeloid leukemias altered adhesive interactions with the bone marrow stroma is involved in the abnormal proliferative behavior and premature release of leukocyte precursors from the bone marrow. Second, genetic defect of the bone marrow stromal microenvironment results in abnormal hematopoiesis most pronounced in the red blood cell development. Third, production of red blood cells and B lymphocytes are excellent models for studying hematopoiesis, and can thus provide insights relevant to a broad range of blood diseases and other biomedical problems. The approaches to be used are: 1) Interaction of leukemic and normal precursors of red blood cells and B lymphocytes with fibronectin, a major adhesive glycoprotein of the bone marrow stroma, will be analyzed using specific adhesive domains of fibronectin and synthetic peptides representing the sequence of fibronectin; 2) Monoclonal antibodies that disrupt these cellular interactions will be identified for the isolation and structural characterization of cell surface molecules involved in these adhesive processes; 3) Cells of the different maturative compartments of B lymphocyte developmental pathway will be isolated from the normal bone marrow to determine their adhesion specificity; and 4) Differentiation of normal progenitors cells into red blood cells will be studied on different adhesive domains of fibronectin to determine the function of these domains in the development of red blood cells.